Pteridine compounds for the treatment of psoriasis

ABSTRACT

The invention provides pteridine compounds of formula (I), processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy. Formula (I) in which A is a group of formula (a) or (b).

[0001] The present invention relates to certain heterocyclic compounds,processes and intermediates used in their preparation, pharmaceuticalcompositions containing them and their use in therapy.

[0002] Chemokines play an important role in immune and inflammatoryresponses in various diseases and disorders, including asthima andallergic diseases, as well as autoinmnune pathologies such as rheumatoidarthritis and atherosclerosis. These small secreted molecules are agrowing superfamily of 8-14 kDa proteins characterised by a conservedcysteine motif. At the present time, the chemokine superfamily comprisesthree groups exhibiting characteristic structural motifs, the C-X-C, C-Cand C-X₃-C families. The C-X-C and C-C families have sequence similarityand are distinguished from one another on the basis of a single aminoacid insertion between the NH-proximal pair of cysteine residues. is TheC-X₃-C family is distinguished from the other two families on the basisof having a triple amino acid insertion between the NH-proximal pair ofcysteine residues.

[0003] The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

[0004] The C-C chemokines include potent chemoattractants of monocytesand lymphocytes but not neutrophils. Examples include human monocytechemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated onActivation, Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

[0005] The C-X₃-C chemokine (also known as fractalkine) is a potentchemoattractant and activator of microglia in the central nervous system(CNS) as well as of monocytes, T cells, NK cells and mast cells.

[0006] Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1,CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CR1 for theC-X₃-C family. These receptors represent good targets for drugdevelopment since agents which modulate these receptors would be usefulin the treatment of disorders and diseases such as those mentionedabove.

[0007] The present invention provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof:

[0008] in which:

[0009] A is a group of formula (a) or (b):

[0010] R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl group, the latter four groups being optionally substitutedby one or more substituent groups independently selected from halogenatoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, an aryl or heteroaryl group both of which can beoptionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸S₂R¹⁰, C₁-C₆ alkyl ortrifluoromethyl groups;

[0011] R² represents hydrogen or a C₃-C₇ carbocyclic group, C₁-C₈ alkyl,C₂-C₆ alkenyl or C₂-C₆ alkynyl group, the latter four groups may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, —OR⁴, —NR⁵R⁶ —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹,—SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ or —NR⁸SO₂R⁹;

[0012] R³ represents hydrogen or C₂-C₆ alkyl optionally substituted byone or more substituent groups independently selected from halogenatoms, phenyl, —OR¹⁰ and —NR¹¹R¹²;

[0013] or

[0014] R² and R³ represent a 3-8 membered ring optionally containing oneor more atoms selected from O, S, NR⁸ and itself optionally substitutedby C₁₋₃-alkyl, halogen or OR⁴;

[0015] R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl group the lattertwo of which may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, phenyl, —OR¹¹ and—NR¹²R¹³;

[0016] R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆alkyl or phenyl group the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶

[0017] or

[0018] R⁵ and R⁶ together with the nitrogen atom to which they areattached form a 4- to 7-membered saturated heterocyclic ring systemoptionally comprising a further heteroatom selected from oxygen andnitrogen atoms, which ring system may be optionally substituted by oneor more substituent groups independently selected from phenyl, —OR¹⁴,—COOR¹⁴, —NR¹⁵R⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ orC₁-C₆ alkyl, itself optionally substituted by one or more substituentsindependently selected from halogen atoms and —NR¹⁵R¹⁶ and —OR⁷ groups;

[0019] R¹⁰ represents a C₁-C₆ alkyl or a phenyl group, each of which maybe optionally substituted by one or more substituent groupsindependently selected from halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶;

[0020] X is O, S or NR⁸;

[0021] Y is CR¹⁸R¹⁹;

[0022] Z is CR²⁰ where R²⁰ represents a C₁-C₆ alkyl or a phenyl group,each of which may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, phenyl, —OR²¹ and—NR²²R²³, or an acyl group selected from CO₂R²¹ or CONR²²R²³; and

[0023] each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²¹, R²² and R²³ independently represent a hydrogen atom, C₁-C₆, alkyl,or a phenyl group.

[0024] In the context of the present specification, unless otherwiseindicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in asubstituent group may be linear or branched.

[0025] Aryl groups include phenyl and naphthyl. Heteroaryl is defined asa 5- or 6-membered aromatic ring optionally containing one or moreheteroatoms selected from N, S, O. Examples include pyridine,pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan.

[0026] Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

[0027] Suitably the group R¹ represents a C₃-C₇ carbocyclic, C_(1-C) ₈alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl group, the latter four groups maybe optionally substituted by one or more substituent groupsindependently selected from halogen atoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, an aryl orheteroaryl group both of which can be optionally substituted by one ormore substituents independently selected from halogen atoms, cyano,nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl or trifluoromethyl groups.Substituents can be present on any suitable position of the R¹, aryl andheteroaryl groups, including nitrogen atoms of heteroaryl groups.Particularly advantageous compounds of formula (I) are those in which R¹represents an optionally substituted benzyl group. More preferably R¹represents benzyl or benzyl substituted by one or more C₁-C₆ alkyl,C₁-C₆ alkoxy, or halogen atoms, still more preferably benzyl substitutedby two fluoro atoms, and most preferably benzyl substituted by twofluoro atoms which are ortho and meta to the benyl CH₂ linkage.

[0028] Suitably R² represents hydrogen or a C₃-C₇carbocyclic group,C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl group, the latter fourgroups may be optionally substituted by one or more substituent groupsindependently selected from halogen atoms, —OR⁴, —NR⁵R⁶ —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ or —NR⁸SO₂R⁹, and R³represents hydrogen or C₂-C₆ alkyl optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁰ and —NR¹¹R¹²; or R² and R³ represent a 3-8 membered ringoptionally containing one or more atoms selected from O, S, NR⁸ anditself optionally substituted by C₁₋₃-alkyl, halogen or OR⁴;

[0029] Preferably one of R² and R³ is hydrogen and the other is C₃-C₄alkyl substituted by one or more hydroxy groups. More preferably one ofR² and R³ is hydrogen and the other is CH(CH₃)CH₂OH, CH(Et)CH₂OH,C(CH₃)₂CH₂OH or CH(CH₂OH)₂. When one of R² and R³ is hydrogen and theother is CH(CH₃)CH₂OH or CH(Et)CH₂OH the resulting compounds of formula(I) are preferably in the form of the (R) isomer. Most preferably one ofR² and R³ is hydrogen and the other is CH(CH₃)CH₂OH.

[0030] When A is a group of formula (a), X represents O, S or NR⁸. WhenX represents NR⁸ then R⁸ is preferably hydrogen or C₁₋₆ alkyl.Preferably X is S. Suitably Y is CR¹⁸R¹⁹, preferably Y is CH₂.

[0031] Preferably A is a group of formula (b) and Z is CR²⁰ mostpreferably Z is CH.

[0032] Particularly preferred compounds of the invention include:

[0033]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(phenylmethyl)thio]-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one

[0034]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0035]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0036]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0037](2R)-2-[[2-[[2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]-propanamide

[0038]2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0039]2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0040]2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0041][(2R)-2-[[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]propyl]-carbamicacid, 1,1-dimethylethyl ester

[0042]4-[[(1R)-2-Amino-1-methylethyl]amino]-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-7(8)-pteridinone,monohydrochloride

[0043]2-[[(3-Chloro-4-methoxyphenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0044]4-[(2-Aminoethyl)amino]-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-7(8H-pteridinone,monotrifluoroacetate

[0045]2-[[(2-Fluoro-4-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0046]2-[[(2-Fluoro-3-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0047]2-[[(3-Fluoro-2-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0048]2-[[[4-(Difluoromethoxy)phenyl]methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0049]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(4-hydroxyphenyl)methyl]thio]-7(8H)-pteridinone

[0050]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(3-methylphenyl)methyl]thio]-7(8H)-pteridinone

[0051]2-[(1,3-Benzodioxol-4-ylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0052]2-[[(2,4-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0053]2-[[(3-Chlorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0054]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone

[0055]4-[[-2-Hydroxy-1-(hydroxymethylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone

[0056]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(5-methyl-2-furanyl)methyl]thio]-7(8H)-pteridinone

[0057]2-[[(2-Fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0058]4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(2-thienyl)methyl)thio]-7(8H)-pteridino

[0059]2-[[(2-Fluorophenyl)methyl]thio]-4-[[-2-hydroxy-1-(hydroxymethylethyl]amino]-7(8H)-pteridinone

[0060]4-[[-2-Hydroxy-1-(hydroxymethyl)ethyl]amino]-2-[(2-thienylmethyl)thio]-7(8H)-pteridinone

[0061]2-[[(2-Fluoro-5-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0062]2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0063]2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0064]2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0065]4-[(2-aminoethyl)amino]-2-[[(2-fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-7(8H)-pteridinone

[0066]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-7(8H)-pteridinone

[0067]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methyl-7(8H)-pteridinone

[0068]2-[[(2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7-oxo-6-pteridinecarboxylicacid ethyl ester

[0069]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(trifluoromethyl)-7(8H)-pteridinone

[0070]2-[[(2,3-Difluorophenyl)methyl]thio]4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinonesodium salt

[0071] 2-[(2,3-difluorobenzyl)thio]-4-(ethylamino)-7(8H)-pteridinone

[0072] 2-[(2,3-difluorobenzyl)thio]-4-(isopropylamino)-7(8H)-pteridinone

[0073](+/−)-4-(sec-butylaniino)-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0074]2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)acetarnide

[0075](+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]-7(8H)-pteridinone

[0076](S)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone

[0077](+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone

[0078](R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]7(8H)-pteridinone

[0079]2-[(2,3-difluorobenzyl)thio]-4-[(3-hydroxypropyl)amino]-7(8H)-pteridinone

[0080]2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxyethyl)(methyl)amino]-7(8H)-pteridinone

[0081]3-[{2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}(methyl)amino]propanenitrile

[0082](R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0083](R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0084]2-[(2,3-difluorobenzyl)thio]-4-[(4-hydroxybutyl)amino]-7(8H)-pteridinone

[0085](+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridin

[0086]2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1,1-dimethylethyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[ethyl(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0087](+/−)-4-[(3-amino-2-hydroxypropyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0088](+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(1,3-dimethylbutyl)amino]-7(8H)-pteridinone

[0089](1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxycyclopentyl)amino]-7(8H)-pteridinone

[0090]2-[(2,3-difluorobenzyl)thio]-4-[(5-hydroxypentyl)amino]-7(8H)-ptenidinone

[0091](+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)butyl]amino}-7(8H)-pteridinone

[0092] (+/−)-methyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)propanoate

[0093]2-[(2,3-difluorobenzyl)thio]-4-[(3-hydroxy-2,2-dimethylpropyl)amino]-7(8H)-pteridinone(1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-{[2-hydroxy-1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0094]4-[bis(2-hydroxyethyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0095]2-[(2,3-difluorobenzyl)thio]-4-{[2-(2-hydroxyethoxy)ethyl]amino}-7(8H)-pteridinone

[0096]2-[(2,3-difluorobenzyl)thio]-4-[(2,2-dimethoxyethyl)amino]-7(8H)-pteridinone

[0097]4-{[2-(diethylamino)ethyl]amino}-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0098](S)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)-2,2-dimethylpropyl]amino}-7(8H)-pteridinone

[0099](R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)-3-methylbutyl]amino}-7(8H)-pteridinone

[0100]2-[(2,3-difluorobenzyl)thio]-4-[(6-hydroxyhexyl)amino]-7(8H)-pteridinone

[0101]2-[(2,3-difluorobenzyl)thio]-4-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-7(8H)pteridinone

[0102] (S)-ethyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro4-pteridinyl}amino)-3-hydroxypropanoate

[0103] and pharmaceutically acceptable salts and solvates thereof.

[0104] According to the invention there is also provided a process forthe preparation of a compound of formula (I) which comprises:

[0105] (a) treatment of a compound of formula (IIA):

[0106]  where R¹ is as defined in formula (I) or is a protectedderivative thereof and L is a leaving group with an amine HNR²R³, or

[0107] (b) treatment of a compound of formula (IIB):

[0108]  where R¹ is as defined in formula (I) or is a protectedderivative thereof and L is a leaving group with an amine HNR²R³, or

[0109] (c) treatment of a compound of formula (IIC):

[0110]  where R¹, R² and R³ are as defined in formula (I) or areprotected derivatives thereof with a thiol R¹SH, or

[0111] (d) treatment of a compound of formula (IID):

[0112]  where R¹ is as defined in formula (I) or is a protectedderivative thereof and L' is a leaving group with an amine HNR²R³, andoptionally thereafter process (a), (b), (c) or (d) and in any order:

[0113] removing any protecting groups

[0114] forming a pharmaceutically acceptable salt.

[0115] The reaction of compounds of formula (IIA) and (IIB) with anamine HNR²R³ can be carried out in a solvent such asN-methyl-pyrrolidinone at a temperature between 0° C. and 150° C.Suitable leaving groups L include halogen, especially chloro or bromo.

[0116] The reaction of compounds (IIC) with a thiol R¹SH can be carriedout in a solvent such as N-methylpyrrolildinone using a base such aspotassium tert-butoxide at a temperature between 0° C. and 150° C.

[0117] The reaction of compounds of formula (IID) with an amine HNR²R³can be carried out using either neat amine HNR²R³ or in a solvent suchas 1-methylimidazole at a temperature between 50° C. and 200° C. with orwithout the assistance of microwave radiation.

[0118] Compounds of formula (IIA) where R¹ is as defined in formula (I)and L is a leaving group such as chlorine may be prepared by treatmentof a compound of formula (IIA) where R¹ is as defined above and L is ahydroxyl group with a halogenating agent such as phosphorus oxychloride.The reaction may be carried out in a at reflux in the presence ofN,N-dimethylaniline.

[0119] Compounds of formula (IIA) where R¹ is as defined in formula (I)and L is a hydroxyl group may be prepared by acid treatment of acompound of formula (III) where R¹ and L are as defined above. Suitableacids include p-toluene sulphonic acid and the reaction may be carriedout in a solvent such as toluene at reflux.

[0120] Compounds of formula (III) where R¹ is as defined in formula (I)and L is a hydroxyl group may be prepared by treatment of a compound offormula (IV) where R¹ and L are as defined above with a reducing agentin the presence of ethyl bromoacetate. The reaction may be carried outin a solvent such as ethanol at room temperature using a reducing agentsuch as sodium borohydride.

[0121] Compounds of formula (IV) where R¹ is as defined in formula (I)and L is a hydroxyl group may be prepared by treatment of a compound offormula (V) where R¹ and L are as defined above with a metal thiocyanatein the presence of bromine. The reaction may be performed in a solventsuch as N,N-dimethylformamide at a temperature between 0° C. and 100° C.in the presence of pyridine using potassium thiocyanate.

[0122] Compounds of formula (V) where R¹ is as defined in formula (I)and L is a hydroxyl group are suitably prepared by reacting a compoundof formula (VI):

[0123] with a compound of formula R¹X where R¹ is as defined above and Xis a leaving group such as bromide in the presence of a base such assodium hydroxide. The reaction may be carried out in aqueous NMP at roomtemperature.

[0124] Compounds of formula (VI) are commercially available.

[0125] Compounds of formula (IIB) where R¹ is as defined in formula (I)and L is a leaving group such as bromo may be prepared by treating acompound of formula (IIB) where R¹ is as defined above and L is NH₂ witha diazotizing agent such as isoamyl nitrite in the presence of ahalogenating agent such as bromoform. The reaction may be performed in asolvent such as DMSO at a temperature between 0° C. and 100° C.

[0126] Compounds of formula (IIB) where R¹ is as defined in formula (I)and L is NH₂ may be prepared by either:

[0127] i) Treatment of a compound of formula (VII):

[0128]  where R¹ and L are as defined above with ethyl glyoxylate in thepresence of a base such as sodium methoxide in a solvent such asmethanol at room temperature, or

[0129] ii) Treatment of a compound of formula (VIII):

[0130] where R¹ and L are as defined above with triethylphosphonoacetate in the presence of a base such as butyllithium. Thereaction may be carried out in a solvent such as DMF at a temperaturebetween 0° C. and 100° C.

[0131] Compounds of formula (VII) where R¹ is as defined in formula (I)and L is NH₂ may be prepared by treating a compound of formula (VIII)where R¹ and L are as defined above with a reducing agent such as sodiumhydrosulphite. The reaction may be carried out in a solvent such aswater at reflux.

[0132] Compounds of formula (VIII) where R¹ is as defined in formula (I)and L is NH₂ may be prepared by treating a compound of formula (IX)where R¹ and L are as defined above with a nitrosating agent such assodium nitrite. The reaction may be performed in a solvent such asaqueous acetic acid at a temperature between 0° C. and 100° C.

[0133] Compounds of formula (IX) where R¹ is as defined in formula (I)and L is NH₂ may be prepared by treating a compound of formula (X) witha compound of formula R¹X where R¹ is as defined above and X is aleaving group such as bromide in the presence of a base such aspotassium tert-butoxide. The reaction may be performed in a solvent suchas DMSO at room temperature.

[0134] Compounds of formula (IIC) where R¹,R² and R³ are as defined informula (I) may be prepared from compounds of formula (I) where R¹,R²and R³ are as defined in formula (I) by treatment with a peracid such asperacetic acid. The reaction may be performed in a solvent such asacetic acid at a temperature between 0° C. and 100° C.

[0135] Compounds of formula (IID) where R¹ is as defined in formula (I)and L is an alkoxy group may be prepared from compounds of formula (IID)where R¹ is as defined in formula (I) and L is a thioalkyl group bytreatment with a suitable alcohol in the presence of a base, Suitablealcohols include isopropanol and the base may be sodium and the reactionmay be performed at a temperature between 0° C. and 150° C.

[0136] Compounds of formula (IID) where R¹ is as defined in formula (I)and L is a thioalkyl group may be prepared from compounds of formula(XI) by sequential treatment with an alkyl halide R¹X followed by ethylglyoxalate in the presence of a base. The reaction may be performed in asolvent such as methanol at a temperature between 0° C. and 150° C.using sodium as the base.

[0137] Compounds of formula (X) and (XI) are commercially available.

[0138] It will be appreciated by those skilled in the art that in theprocesses of the present invention certain functional groups such ashydroxyl or amino groups in the starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula (I) may involve, at anappropriate stage, the removal of one or more protecting groups. Theprotection and deprotection of functional groups is fully described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

[0139] Novel intermediate compounds form a further aspect of theinvention. In particular compounds of formula (IIA) and (IIB) are noveland form an aspect of the invention.

[0140] The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably a basicaddition salt such as sodium, potassium, calcium, aluminium, lithium,magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine,ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or anacid addition salt such as a hydrochloride, hydrobromide, phosphate,acetate, fuimarate, maleate, tartrate, citrate, oxalate,methanesulphonate or p-toluenesulphonate.

[0141] The compounds of formula (I) have activity as pharmaceuticals, inparticular as modulators of chemokine receptor (especially CXCR2)activity, and may be used in the treatment (therapeutic or prophylactic)of conditions/diseases in human and non-human animals which areexacerbated or caused by excessive or unregulated production ofchemokines. Examples of such conditions/diseases include:

[0142] (1) (the respiratory tract) obstructive airways diseasesincluding chronic obstructive pulmonary disease (COPD); asthma, such asbronchial, allergic, intrinsic, extrinsic and dust asthma, particularlychronic or inveterate asthma (e.g. late asthma and airwaysbyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitisand chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa;membranous rhinitis including croupous, fibrinous and pseudomembranousrhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitisnervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lungand related diseases, fibroid lung and idiopathic interstitialpneumonia;

[0143] (2) (bone and joints) rheumatoid arthritis, seronegativespondyloarthropathies (including ankylosing spondylitis, psoriaticarthritis and Reiter's disease), Beheet's disease, Sjogren's syndromeand systemic sclerosis;

[0144] (3) (skin) psoriasis, atopical dermatitis, contact dermatitis andother eczmatous dermitides, seborrhoetic dermatitis, Lichen planus,Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria,angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis,Alopecia areata and vernal conjunctivitis;

[0145] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, food-related allergies which have effects remote from the gut,e.g., migraine, rhinitis and eczema;

[0146] (5) (central and peripheral nervous system) Neurodegenerativediseases and dementia disorders, e.g. Alzheimer's disease, amyotrophiclateral sclerosis and other motor neuron diseases, Creutzfeldt-Jacob'sdisease and other prion diseases, HIV encephalopathy (AIDS dementiacomplex), Huntington's disease, frontotemporal dementia, Lewy bodydementia and vascular dementia; polyneuropathies, e.g. Guillain-Barresyndrome, chronic inflammatory demyelinating polyradiculoneuropathy,multifocal motor neuropathy, plexopathies; CNS demyelination, e.g.multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis,and subacute sclerosing panencephalitis; neuromuscular disorders, e.g.myasthenia gravis and Lambert-Eaton syndrome; spinal diorders, e.g.tropical spastic paraparesis, and stiff-man syndrome: paraneoplasticsyndromes, e.g. cerebellar degeneration and encephalomyelitis; CNStrauma; migraine; and stroke.

[0147] (6) (other tissues and systemic disease) atherosclerosis,Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemiclupus, erythematosus, Hashimoto's thyroiditis, type I diabetes,nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,lepromatous leprosy, and idiopathic thrombocytopenia pupura;post-operative adhesions, and sepsis.

[0148] (7) (allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin and cornea; and chronic graft versus host disease;

[0149] (8) Cancers, especially non-small cell lung cancer (NSCLC),malignant melanoma, prostate cancer and squamous sarcoma, and tumourmetastasis;

[0150] (9) Diseases in which angiogenesis is associated with raisedCXCR2 chemokine levels (e.g. NSCLC, diabetic retinopathy).

[0151] (10) Cystic fibrosis, re-perfusion injury in the heart, brain,peripheral limbs and other organs.

[0152] (11) Burn wounds & chronic skin ulcers

[0153] (12) Reproductive Diseases (e.g. Disorders of ovulation,menstruation and implantation, Pre-term labour, Endometriosis)

[0154] Thus, the present invention provides a compound of formula (I),or a pharmaceutically-acceptable salt or solvate thereof, ashereinbefore defined for use in therapy.

[0155] Preferably the compounds of the invention are used to treatdiseases in which the chemokine receptor belongs to the CXC chemokinereceptor subfamily, more preferably the target chemokine receptor is theCXCR2 receptor,

[0156] Particular conditions which can be treated with the compounds ofthe invention are psoriasis, diseases in which angiogenesis isassociated with raised CXCR2 chemokine levels, and COPD. It is preferredthat the compounds of the invention are used to treat psoriasis.

[0157] As a further aspect of the present invention, certain compoundsof formula (I) may have utility as antagonists of the CX3CR1 receptor.Such compounds are expected to be particularly useful in the treatmentof disorders within the central and peripheral nervous system and otherconditions characterized by an activation of microglia and/orinfiltration of leukocytes (e.g. stroke/ischemia and head trauma).

[0158] In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for use in therapy.

[0159] In a still further aspect, the present invention provides the useof a compound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined in the manufacture of amedicament for the treatment of human diseases or conditions in whichmodulation of chemokine receptor activity is beneficial.

[0160] In the context of the present specification, the term “therapy”also includes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

[0161] The invention still further provides a method of treating achemokine mediated disease wherein the chemokine binds to a chemokine(especially CXCR2) receptor, which comprises administering to a patienta therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

[0162] The invention also provides a method of treating an inflammatorydisease, especially psoriasis, in a patient suffering from, or at riskof, said disease, which comprises administering to the patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

[0163] For the above-mentioned therapeutic uses the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration, the treatment desired and the disorder indicated.

[0164] The compounds of formula (I) and pharmaceutically acceptablesalts and solvates thereof may be used on their own but will generallybe administered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

[0165] The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

[0166] The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined, with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

[0167] The pharmaceutical compositions may be administered topically(e.g. to the lung and/or airways or to the skin) in the form ofsolutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally. Preferably the compounds of theinvention are administered orally.

[0168] The invention will now be further illustrated by reference to thefollowing examples. In the examples the Nuclear Magnetic Resonance (NMR)spectra were measured on a Varian Unity Inova 300 or 400 MHzspectrometer and the Mass Spectrometry (MS) spectra measured on aFinnigan Mat SSQ7000 or Micromass Platform spectrometer. Wherenecessary, the reactions were performed under an inert atmosphere ofeither nitrogen or argon. Chromatography was generally performed usingMatrex Silica 60® (35-70 micron) or Prolabo Silica gel 60® (35-70micron) suitable for flash silica gel chromatography. High pressureliquid chromatography purification was performed using either a WatersMicromass LCZ with a Waters 600 pump controller, Waters 2487 detectorand Gilson FC024 fraction collector or a Waters Delta Prep 4000. Theabbreviations m.p. and DMSO used in the examples stand for melting pointand dimethyl sulphoxide respectively.

EXAMPLE 14-[[((1R)-2-Hydroxy-1-methylethyl]amino]-2-[(phenylmethyl)thio]-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one,

[0169] (a)6-Amino-1,4-dihydro-2-[(phenyluaethyl)thio]-4-oxo-5-thiocyanic acid,pyrimidinyl ester

[0170] 6-Amino-2-[(phenylmethyl)thio]-4(1H)-pyrimidinone (10.5g)[preparation as described in WO 9635678] and potassium thiocyanate (25g) in N,N-dimethylformamide (200 ml) were heated together at 65° C.Pyridine (6.3 ml) was added and the solution cooled to 5° C. Bromine(2.2 ml) was added slowly and the reaction mixture stirred for 2 hoursat 5-10° C. The reaction mixture was poured onto ice water, stirred for1 hour and the solid was isolated by filtration. After washing withwater and ether, a pure sample was obtained after trituration with hotmethanol.

[0171] MS (APCI) 291 (M+H, 100%).

[0172] (b)[[6-amino-1,4-dihydro-4-oxo-2-[(phenylmethyl)thio]-5-pyrimidinyl]thio]-aceticacid, ethyl ester

[0173] To a suspension of the product from step a) (1.5 g) in dryethanol (100 ml) was added sodium borohydride (0.570 g) and theresultant solution allowed to stir for 15 mins.

[0174] To this solution was added ethyl bromoacetate (0.570 ml). Themixture was neutralised with concentrated hydrochloric acid thenevaporated to dryness and purified (SiO₂, ethyl acetate: dichloromethane1:1 as eluant) to give the subtitle compound as a colourless solid (1.1g).

[0175] MS (APCI) 352 (M+H, 100%).

[0176] (c)2-[(Phenylmethyl)thio]-1H-pyrimido[5,4-b][1,4]thiazine-4,7(6H,8H)-dione

[0177] To a solution of the product from step b) (0.30 g) in dry toluene(60 ml) was added p-toluene sulphonic acid (50 mg) and the solutionheated under reflux for 11 hours. The resultant solid was collected byfiltration, washed with ether and dried to give the subtitle compound asa colourless solid (0.290 g)

[0178] MS (APCI) 306 (M+H, 100%).

[0179] (d)4-Chloro-2-[(phenylmethyl)thio]-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one

[0180] A suspension of the product from step c) (1.5 g), phosphorusoxychloride (10 ml) and N,N-dimethyl aniline (1 ml) was heated underreflux for 2 hours. The mixture was allowed to cool to room temperatureand poured carefully into a saturated sodium bicarbonate solution, andstirred for 15 mins. The crude product was extracted into ethyl acetateand purified (SiO₂, dichloromethane as eluant) to give the subtitlecompound (0.25 g)

[0181] MS (APCI) 324 (M+H⁺, 100%).

[0182] (e)4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(phenylmethyl)thio]-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one,

[0183] The product from step e) (0.250 g) in NMP (5 ml) was treated with(R)-2-amino-1-propanol (0.116 g) and the reaction mixture was heated at110° C. for 2 hours. The mixture was evaporated to dryness and theresidue purified (HPLC, Symmery® C18 column, 0.1% aqueous ammoniumacetate:acetonitrile isocratic elution 75:25) to afford the titlecompound (0.13 g).

[0184] MS: APCI 363 (M+H)

[0185]¹H NMR: δ(DMSO) 10.84 (1H, s), 7.47-7.19 (5H, m), 6.26 (1H, d),4.78 (1H, t), 4.36-4.19 (3H, m), 3.55-3.32 (4H, m), 1.12 (3H, d).

EXAMPLE 22-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0186] a) 2-[[(2,3-Difluorophenyl)methyl]thio]-4,6-pyrimidinediamine

[0187] 4,6-diarnino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100ml) at room temperature under an atmosphere of nitrogen. Potassiumtert-butoxide (1M in THF, 48.3 ml) was added followed by2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hoursat room temperature. The reaction mixture was then partitioned betweenethyl acetate and ammonium chloride. The organic phase was washed withammonium chloride (3×) and brine, then dried over magnesium sulphate andevaporated to give the subtitled product as a white solid (12.2 g)

[0188] MS: ADCI (+ve) 269 (M+1)

[0189] b)2-[[(2,3-Difluorophenyl)methyl]thio]-5-nitroso-4,6-pyrimidinediamine

[0190] The product of step (a) (2.5 g) was dissolved in acetic acid (150ml) and the solution cooled to 5° C. A solution of sodium nitrite (625mg) in water (50 ml) was added dropwise resulting in a dark bluecolouration. The reaction was stirred at room temperature for 30 minutesduring which time a pink solid precipitated from solution. This wasisolated by filtration and washed with water, then dried at 50° C. togive the sub-titled product as a blue solid (4.14 g)

[0191] MS: ADCI (+ve) 298 (M+1)

[0192]¹H NMR: δ(DMSO) 4.44 (s,2H), 7.13-7.54 (m,3H), 8.13 (s,1H), 8.51(s,1H), 9.10 (s,1H), 10.18 (s,1H).

[0193] c) 2-[[(2,3-Difluorophenyl)methyl]thio]-4,5,6-pyrimidinetriamine

[0194] To a suspension of the product of step (b) (2 g) in boiling water(40 ml) was added Na₂S₂O₄ (5.4 g) portion-wise. The suspension wasallowed to cool and then 50% sulphuric acid was added slowly and thenthe mixture was cooled to 0° C. The solid was isolated by filtration andwashed with cold water, then dried over P₂O₅ at 50° C. to give thesub-titled product as a yellow solid.

[0195] MS: ADCI (+ve) 284 (M+1)

[0196]¹H NMR: δ(DMSO) 4.33 (s,2H), 6.42 (brs,3H), 7.10-7.48 (m,3H)

[0197] d) 4-amino-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

[0198] The product of step (c) (100 mg) was dissolved in a solution ofsodium (0.05 g) in methanol (5 ml). This was left to stir for 15 min atroom temperature, then ethyl glyoxalate (134 μl) was added to themixture which was left to stir for 12 hr at room temperature.

[0199] Water (5 ml) was added, then concentrated hydrochloric acid wasslowly added to acidify the solution to ˜pH5 whereupon a solidprecipitated which was isolated by filtration and dried over P₂O₅ at 50°C. to yield a pale yellow solid (44.5 mg).

[0200] MS: ADCI (+ve) 322 (M+1)

[0201]¹H NMR: δ(DMSO) 4.18 (s,2H), 7.11-7.58 (m,3H), 7.84 (s,1H), 12.69(bs,1H)

[0202] e) 4-bromo-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

[0203] The product of step (d) (6.0 g) was suspended in DMSO (90 ml) andbromoform (60 ml) was added and the mixture was heated to 100° C.Isopentylnitrite (25 ml) was added and the mixture stirred for 5 min.The mixture was quickly cooled in an ice bath then evaporated to leavean oil. This was repeated three times. Acetonitrile (200 ml) was addedand the solid which separated was removed by filtration. The solvent wasevaporated and the residue was purified by flash chromatography, elutingwith dichloromethane and then 5% ethyl acetate in dichloromethane togive a yellow solid which was slurried with ether then collected. Thesolid was washed with ether and dried to give the subtitled compound asa colourless solid (8.74 g).

[0204] MS: APCI (−ve) 382/4 (M-H), 382 (100%)

[0205]¹H NMR: δ(DMSO) 4.47 (s, 2H), 7.13-7.55 (m,3H), 8.14 (s,1H), 13.33(bs,1H)

[0206] f)2-[[(2,3-difluorophertyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0207] The product of step (e) (8.7 g) was dissolved inN-methylpyrrolidinone (40 ml) and Hunigs base (7.9 ml) was addedfollowed by D-alaninol (2.7 ml). The mixture was stirred at 100° C. for15 mins. The cooled solution was poured onto water, (11), and acidifiedwith dilute hydrochloric acid. The solid which separated was collected,washed with water and air dried. Crystallisation from acetonitrileafforded the title compound as a pale yellow solid (7.4 g).

[0208] m.p. 215-217° C.

[0209] MS: APCI (+ve) 380 (M+H, 100%)

[0210]¹H NMR: δ(DMSO) 1.14 (d, 3H), 3.48 (m, 2H), 4.31 (m, 1H), 4.45(dd, 2H) 4.82 (t, 1H) 7.15 (m, 1H), 7.33 (m, 1H), 7.47 (t, 1H), 7.76 (d,1H), 7.83 (d,1H), 12.70 (s, 1H).

[0211] Alternatively, example 2 may be prepared by the followingprocedure:

[0212] g) 2,4-bis[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

[0213] Sodium (3.96 g) was dissolved in methanol (150 ml),5,6-diamino-2,4-pyrimidinedithiol (15 g) was added, then2,3-difluorobenzylbromide (30.9 g) slowly added and the reaction mixturewas stirred at room temperature under nitrogen for 10 min. Ethylglyoxalate (1 5 ml) was added followed by more sodium (2.5 g) and thereaction was left for a further 20 min. The reaction was then quenchedwith acetic acid (10 ml) and poured on to water (600 ml) with stirring.The resulting precipitate was filtered through celite and washed withwater. The filtrate was discarded and the solid was washed through thecelite using acetone. The solution was then evaporated to dryness andpurified by silica gel column chromatography using 10% ethyl acetate inDCM to yield the sub-titled compound as a cream solid (8 g).

[0214] MS: APCI (+ve) 465 (M+1)

[0215] h)2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0216] The product of example 2, step (g) (2.3 g) and D-alaninol (5 g)were microwaved at 150° C. for 5 min. The resulting solution waspartitioned between ethyl acetate and aqueous ammonium chloride and theorganic layer was washed with ammonium chloride (2×50 ml). The organiclayer was evaporated to dryness and purified twice by silica gelchromatography using first 20:1 DCM:methanol and then 1:1 DCM:ethylacetate to yield the titled compound (220 mg).

[0217] MS: APCI (+ve) 380 (M+1)

EXAMPLE 32-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0218] a) 4-amino-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

[0219] To a solution of triethyl phosphonoacetate (15.0 g) intetrahydrofuran (60 ml) cooled in an ice bath was added butyllithium(2.5M in hexanes, 25.6 ml) at a rate such that the internal temperaturewas maintained below 30° C. To this mixture was then added a solution ofthe product of Example 2 step (b) (10.0 g) in N,N-dimethylformamide (60ml). The reaction mixture was heated at reflux for 1 hour, then cooledto room temperature and quenched with acetic acid (6 ml). The solid thusprecipitated was isolated by filtration, washed with water, ethanol anddiethyl ether, and dried over P₂O₅ at 50° C. to give the sub-titledproduct as a pale green solid (9.3 g).

[0220] MS: ADCI (+ve) 322 (M+1)

[0221]¹H NMR: δ(DMSO) 4.18 (s,2H), 7.11-7.58 (m,3H), 7.84 (s,1H), 12.69(bs,1H)

[0222] b) 4-bromo-2-[[(2,3-difluorophenyl)methyl]thio]-7(8H)-pteridinone

[0223] The product of step (a) (0.5 g) was suspended in DMSO (10 ml) andbromoform (10 ml) and the mixture was heated to 125° C. Isoamylnitrite(2 ml) was added and the mixture was stirred at 125° C. for 5 minutesbefore being cooled in an ice bath. Solvent was removed by evaporationunder high vacuum and the residue suspended in dichloromethane (100 ml).This suspension was washed with saturated aqueous ammonium chloride (50ml) and then filtered through a plug of celite. The filtrate wasevaporated and purified by column chromatography, eluting with 10% ethylacetate in dichloromethane to give the subtitled compound as a whitesolid (0.22 g).

[0224] MS: ADCI (+ve) 386 (M+1)

[0225]¹H NMR: δ(DMSO) 4.47 (s,2H), 7.13-7.55 (m,3H), 8.14 (s,1H), 13.33(bs,1H)

[0226] c)2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0227] The titled compound (57 mg) was prepared from the product of step(b) (80 mg) and 2-amino-1,3-propanediol (29 mg) using the method ofExample 2 step (f).

[0228] MS: ADCI (+ve) 396 (M+1)

[0229]¹H NMR: δ(DMSO) 12.73 (1H, br s), 7.85 (1H, s), 7.50 (2H, m), 7.33(1H, m), 7.15 (1H, m), 4.80 (2H, t), 4.45 (2H, s), 4.23 (1H, m), 3.55(4H, m).

EXAMPLE 42-[[(2,3-Difluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0230] The titled compound (52 mg) was prepared from the product ofExample 3 step (b) (150 mg) and ethanolamine (35 ul) using the method ofExample 2 step (f).

[0231] MS: ADCI (+ve) 366 (M+1)

[0232]¹H NMR: δ(DMSO) 12.71 (1H, br s), 8.09 (1H, br t), 7.84 (1H, s),7.47 (1H, m), 7.32 (1H, m), 7.16 (1H, m), 4.78 (1H, t), 4.45 (2H, s),3.53 (4H, m).

EXAMPLE 5(2R)-2-[[2-[[2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]-propanamide

[0233] The titled compound (160 mg) was prepared from the product ofExample 3 step (b) (500 mg) and D-alanine amide hydrochloride (172 mg)using the method of Example 2 step (f).

[0234] MS: ADCI (+ve) 393 (M+1)

[0235]¹H NMR: δ(DMSO) 12.77 (1H, br s), 7.88 (1H, s), 7.85 (1H, d), 7.55(1H, br s), 7.47 (1H,t), 7.36 (1H, m), 7.19 (1H, br s), 7.16 (1H, m),4.60 (1H, q), 4.46 (2H, q), 1.40 (3H, d).

EXAMPLE 62-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0236] a) 4-Amino-2-[(phenylmethyl)thio]-7(8H)-pteridinone

[0237] The subtitled compound (16.5 g) was prepared by the method ofExample 3, step (a) using5-nitroso-2-[(phenylmethyl)thio]-4,6-pyrimidinediamine (22.5 g).

[0238] MS (ESI) 286 (M+H, 100%).

[0239] b) 4-Amino-2-[(phenylmethyl)sulfonyl]-7(8H)-pteridinone

[0240] A suspension of the product from example 6, step (a) (5.00 g) inacetic acid (500 ml) and peracetic acid (36.40 wt. % solution in aceticacid, 50 ml) was stirred at 50° for 1 hour. After quenching withdimethylsulphide (15 ml) the solution was poured into ice-water (5000ml). The suspended solid was removed by filtration and dried in-vacuo togive the subtitled compound as a pale yellow powder (4.53 g).

[0241] MS (ESI) 316 (M−H, 100%).

[0242] c) 3-Chloro-2-fiuoro-benzenemethanethiol

[0243] 3-Chloro-2-fluorobenzyl bromide (1.00 g) and thiourea (0.35 g)were heated together at reflux in ethanol (10 ml) for 1 hour. Thesolvent was removed in-vacuo and the residue was suspended in 10%aqueous sodium hydroxide (10 ml) and heated at reflux for 3 hours. Thesolution was then acidified with conc. HCl and extracted into ether.Concentration of the organic phase ini-vacuo gave the subtitle compoundas a pale yellow oil (0.71 g).

[0244] MS (EI) 176/178 (M+), 143/145 (100%).

[0245] d)4-Amino-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-7(8H)-pteridinone

[0246] The product from example 6, step (c) (0.63 g) and 1M t-butoxidesolution in THF (3.5 ml) were added to a suspension of the product fromexample 6, step (b) (1.11 g) in NMP (20 ml). The mixture was stirredvigorously for 1 hour, poured into 1M HCl (15 ml) and diluted withwater. The suspended solid was removed by filtration and dried in-vacuoto give the subtitled compound as a pale yellow powder (1.14 g).

[0247] MS (ESI) 338 (M+H, 100%).

[0248] e)4-Bromo-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-7(8H)-pteridinone

[0249] The subtitled compound (0.318 g) was prepared by the method ofExample 3, step (b) using the product from example 6, step (d) (1.10 g).

[0250] MS (ESI) 399/401 (M−H, 100%).

[0251] f)2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8,H)-pteridinone

[0252] The titled compound was prepared by the method of Example 2, step(f) using the product from example 6, step (e) (75 mg). The reactionmixture was poured into water and acidified with conc. HCl. Thesuspended solid was removed by filtration, dried in air andrecrystallized from acetonitrile to give a yellow solid (37 mg).

[0253] m.p. 209-211°

[0254] MS (APCI) 396 (M+H, 100%).

[0255]¹H NMR: δ(DMSO) 12.71 (1H, br s), 7.83 (1H, s), 7.76 (1H, d), 7.64(1H, t), 7.48 (1H, t), 7.17 (1H, t), 4.82 (1H, t), 4.39-4.48 (2H, m),4.28 (1H, m), 3.40-3.52 (2H, m), 1.13 (3H, d).

EXAMPLE 72-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0256] The titled compound (51 mg) was prepared by the method of Example6, step (f) using the product from Example 6, step (e) (75 mg) andethanolamnine (25 ul).

[0257] m.p. 195-196.50°

[0258] MS (APCI) 382 (M+H, 100%).

[0259]¹H NMR: δ(DMSO) 12.71 (1H, br s), 8.08 (1H, br m), 7.84 (1H, s),7.64 (1H, t), 7.49 (1H, t), 7.17 (1H, t), 4.79 (1H, br m), 4.44 (2H, s),3.53 (4H,br m).

EXAMPLE 82-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0260] The titled compound (51 mg) was prepared by the method of Example6, step (f) using the product from Example 6, step (e) (75 mg) and2-amino-1,3-propanediol (37 mg).

[0261] m.p. 218.5-220.5°

[0262] MS (APCI) 412 (M+H, 100%).

[0263]¹H NMR: δ(DMSO) 12.74 (1H, br s), 7.85 (1H, s), 7.67 (1H, t), 7.50(2H, m), 7.16 (1H, t), 4.81 (2H, t), 4.44 (2H, s), 4.24 (1H, m),3.51-3.62 (4H, m).

EXAMPLE 9[(2R)-2-[[2-[[3-Chloro-2-fluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]propyl]-carbamicacid, 1,1-dimethylethyl ester

[0264] (a) [(1R)-2-amino-1-methyl-2-oxoethyl]carbamic acid,9H-fluoren-9-ylmethyl ester

[0265] A solution of D-Alaninamide hydrochloride (3 g) in 10% sodiumcarbonate solution (50 ml) and dioxan (50 ml) was treated with FMOCchloride (6.24 g) in dioxane (40 ml) and allowed to stir overnight. Themixture was diluted with water (500 ml) and the product collected byfiltration and dried in vacuo to give 9.0 g of the subtitle compound.

[0266] MS (ESI) BP 311 (+H)

[0267] (b) [(1R)-2-amino-1-methylethyl]carbamic acid,9H-fluoren-9-ylmethyl ester

[0268] To a solution of the product from example 9, step (a) (6.9 g) inTHF (100 ml) was added borane-methylsulfide complex (4.4 ml) and themixture heated under reflux for 2 hours. The mixture was carefuillyquenched by the addition of methanol (100 ml), evaporated to dryness andthe residue taken up into methanol (100 ml) and acidified to pH 1-2 withconcentrated hydrochloric acid. Heated under reflux for 30 mins thenevaporated to dryness. The residue was triturated with ether to give asolid, which was collected by filtration, dissolved in water and thefree base precipitated by the addition of aqueous sodium bicarbonatesolution to give the subtitle compound (3.1 g).

[0269] MS (ESI) BP 297 (+H)

[0270] (c) (2R)-[2-(9H-Fluoren-9-ylmethoxycarbonylamino)-propyl]carbamicacid, 1,1-dimethylethylester.

[0271] To a stirred solution of the product from example 9, step (b)(3.0g) in THF (100 ml) was added ditert-butyldicarbonate (2.2 g) and themixture stirred at room temp for 30 mins. The mixture was evaporated todryness and the crude product purified (SiO₂, dichloromethane as eluant)to give the subtitle compound (3.8 g).

[0272] NMR δH (CDCl₃) 7.76 (2H, m), 7.42 (2H, m), 7.39-26 (4H, s), 5.01(1H, s), 4.85 (1H, s), 4.38 (2H, d), 4.19 (1H, t), 3.77 (1H, m), 3.18(2H, m), 1.27 (9H, s).

[0273] (d) [(2R)-2-aminopropyl]carbamic acid, 1,1-dimethylethyl ester

[0274] To a solution of the product from example 9, step (c) (3.8 g) inTHF (100 ml) was added piperidine (5 ml) and the mixture allowed tostand for 1 hour at room temp. The mixture was evaporated to dryness andthe residue purified (SiO₂, 5% methanol:dichloromethane as eluant) togive the subtitle compound as a colourless oil (1.7 g).

[0275] NMR δH (CDCl₃) 4.95 (1H, s), 3.13 (1H, m), 2.99 (1H, m), 2.87(1H, m), 1.38 (9H, s), 1.08 (3H, d).

[0276] (e)[(2R)-2-[[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]propyl]-carbamicacid, 1,1-dimethylethyl ester

[0277] The titled compound (83 mg) was prepared by the method of Example6, step (f) using the product from Example 6, step (e) (75 mg) and theproduct from example 9, step (d) (72 mg).

[0278] MS (APCI) 495 (M+H, 100%).

[0279]¹H NMR: δ(DMSO) 7.95 (1H, br d), 7.83 (1H, s), 7.62 (1H, t), 7.48(1H, t), 7.17 (1H, t), 6.94 (1H, br t), 4.34-4.53 (3H, m), 3.04-3.17(2H, m), 1.32 (9H, s), 1.11 (3H, d).

EXAMPLE 104-[[(1R)-2-Amino-1-methylethyl]amino]-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-7(8H)-pteridinone,monohydrochloride

[0280] A two-phase mixture of the product from Example 9 (76 mg) in1,4-dioxane (3 ml) and conc. HCl (0.3 ml) was stirred for 2 hours, thendiluted with water (10 ml) and lyophilised. The residue was dissolved inwater (10 ml), washed with ethyl acetate (5 ml), and lyophilised to givethe titled compound as a pale yellow solid (58 mg).

[0281] MS (APCI) 395 (M+H parent amine, 100%).

[0282]¹H NMR: δ(D₂O) 7.86 (1H, s), 7.35 (1H, br t), 7.18 (1H, br t),6.95 (1H, br t), 4.62 (1H, m), 4.20-4.41 (2H, m), 3.14-3.29 (2H, m),1.33 (3H, br d).

EXAMPLE 112-[[(3-Chloro-4-methoxyphenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0283] a)4-Amino-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-7(8H)-pteridinone

[0284] The subtitled compound (1.36 g) was prepared by the method ofExample 6, step (d) using the product from Example 6, step (b) (1.21 g)and 3-chloro-4-methoxy-benzenemethanethiol (0.72 g).

[0285] MS (ESI) 350 (M+H, 100%).

[0286] b)4-Bromo-2-[[(3-chloro4-methoxyphenyl)methyl]thio]-7(8H)-pteridinone

[0287] The subtitled compound (0.28 g) was prepared by the method ofExample 3, step (b) using the product from example 11, step (a) (1.25g).

[0288] MS (ESI) 411/413 (M−H, 100%).

[0289] c)2-[[(3-Chloro-4-methoxyphenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0290] The titled compound (89 mg) was prepared by the method of Example8 using the product from example 11, step (b) (0.100 g).

[0291] m.p. 209-211°

[0292] MS (APCI) 424 (M+H, 100%).

[0293]¹H NMR: δ(DMSO) 12.73 (1H, s), 7.85 (1H, s), 7.54 (1H, d), 7.45(2H, m), 7.06 (1H, d), 4.81 (2H, br), 4.33 (2H, s), 4.20-4.28 (1H, m),3.82 (3H, s), 3.51-3.63 (4H, m).

EXAMPLE 124-[(2-Aminoethyl)amino]-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-7(8H)-pteridinone,monotrifluoroacetate

[0294] The titled compound (15 mg) was prepared by the method of Example2, step (f) using the product from Example 11 step (b) (50 mg) andethylenediamine (24μl). The reaction mixture was diluted with water (150ml), lyophilised to give a solid, and purified (HPLC, Symmetry® C8column, 0.1% aqueous trifluoroacetic acid:acetonitrile, isocraticelution 75:25).

[0295] MS (APCI) 393 (M+H parent amine, 100%).

[0296]¹H NMR: δ(D₂O) 7.89 (1H, s), 7.39 (1H, s), 7.28 (1H, d), 6.92 (1H,d), 4.23 (2H, s), 3.84 (5H, m), 3.25 (2H, br t).

EXAMPLE 132-[[(2-Fluoro-4-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8,H)-pteridinone

[0297] a)2-[[(2,3-Difluorophenyl)methyl]sulfonyl]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0298]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone(0.38 g) was stirred in acetonitrile (150 ml) and water (150 ml) withoxone (3.79 g) for 18 hrs. Acetonitrile was removed in vacuo to leave anaqueous suspension. The solid was collected and dried in vacuo to affordthe subtitled compound (0.30 g).

[0299] MS (APCI) 412 (M+H) (100%)

[0300] b) 2-Fluoro4-methoxy-benzenemethanethiol

[0301] The subtitled compound (0.33 g) was prepared by the method ofExample 6, step (c) using 1-(chloromethyl)-2-fluoro-4-methoxy-benzene(0.56 g).

[0302] MS (EI) 172 (M+), 139 (100%).

[0303] c)2-[[(2-Fluoro-4-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0304] The titled compound was prepared by the method of Example 6, step(d) using the product from example 13, step (a) (0.20 g), the productfrom example 13, step (b) (0.10 g) and DMSO (2 ml) instead of NMP assolvent. The reaction mixture was purified (HPLC, Synunetrye® C8 column,0.1% aqueous amnmonium acetate:acetonitrile, gradient elution 80:20 to20:80) to give a white solid (63 mg).

[0305] MS (APCI) 392 (M+H, 100%).

[0306]¹H NMR: δ(DMSO) 12.69 (1H, br s), 7.83 (1H, s), 7.75 (1H, br d),7.53 (1H, t), 6.83 (1H, d), 6.72 (1H, d), 4.83 (1H, br t), 4.34 (3H, m),3.75 (311, s), 3.41-3.54 (2H, m), 1.16 (3H, d).

EXAMPLE 142-[[(2-Fluoro-3-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0307] a) 2-Fluoro-3-methyl-benzenemethanethiol

[0308] The subtitled compound (0.36 g) was prepared by the method ofExample 6, step (c) using 2-fluoro-3-methyl-benzyl bromide (0.55 g).

[0309] MS (EI) 156 (M+), 123 (100%).

[0310] b)2-[[(2-Fluoro-3-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0311] The titled compound (56 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) andthe product from example 14, step (a) (94 mg).

[0312] MS (APCI) 376 (M+H, 100%).

[0313]¹H NMR: δ(DMSO) 12.69 (1H, br s), 7.83 (1H, s), 7.76 (1H, d), 7.43(1H, t), 7.18 (1H, t), 7.02 (1H, t), 4.83 (1H, t), 4.28-4.43 (3H, m),3.41-3.54 (2H, m), 2.23 (3H, d).

EXAMPLE 152-[[(3-Fluoro-2-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0314] a) 1-(Chloromethyl)-3-fluoro-2-methoxy-benzene

[0315] A solution of 3-fluoro-2-methoxy-benzenemethanol (WO 20000419)(0.50 g) and thionyl chloride (0.47 ml) in dichloromethane (30 ml) wasstirred for 2 hours then concentrated in-vacuo to give the subtitledcompound, which was used directly in the next step.

[0316] b) 3-Fluoro-2-methoxy-benzenemethanethiol

[0317] The subtitled compound (0.31 g) was prepared by the method ofExample 6, step (c) using the product from example 15, step (a).

[0318] MS (EI) 172 (M+), 139 (100%).

[0319] c)2-[[(3-Fluoro-2-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0320] The titled compound (84 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) andthe product from example 15, step (b) (0.10 g).

[0321] MS (APCI) 392 (M+H, 100%).

[0322]¹H NMR: δ(DMSO) 12.69 (1H, br s), 7.83 (1H, s), 7.76 (1H, d), 7.37(1H, d), 7.18 (1H, m), 7.03 (1H, m), 4.83 (1H, br t), 4.31-4.42 (3H, m),3.91 (3H, s), 3.42-3.53 1.16 (3H, d).

EXAMPLE 162-[[[4-(Difluoromethoxy)phenyl]methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0323] a) 4-(Difluoromethoxy)-benzenemethanethiol

[0324] The subtitled compound (0.20 g) was prepared by the method ofExample 6, step (c) using 4-(difluoromethoxy)-benzyl bromide (0.53 g).

[0325] MS (EI) 190 (M+), 107 (100%).

[0326] b)2-[[[4-(Difluoromethoxy)phenyl]methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0327] The titled compound (51 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) andthe product from example 16, step (a) (0.17 g).

[0328] MS (APCI) 410 (M+H, 100%).

[0329]¹H NMR: δ(DMSO) 12.67 (1H, br s), 7.82 (1H, s), 7.74 (1H, d), 7.53(2H, d), 7.19 (1H, t), 7.10 (2H, d), 4.82 (1H, t), 4.28-4.41 (3H, m),3.39-3.52 (2H, m), 1.15 (3H, d).

EXAMPLE 174-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(4-hydroxyphenyl)methyl]thio]-7(8H)-pteridinone

[0330] The titled compound (8 mg) was obtained as a by-product duringthe preparation of Example 16.

[0331] MS (APCI) 360 (M+H, 100%).

[0332]¹H NMR: δ(DMSO) 12.60 (1H, br), 9.35 (1H, s), 7.81 (1H, s), 7.70(1H, d), 7.24 (2H, d), 6.68 (2H, d), 4.83 (1H, t), 4.23-4.36 (3H, m),3.44-3.55 (2H, m), 1.17 (3H, d).

EXAMPLE 184-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(3-methylphenyl)methyl]thio]-7(8H)-pteridinone

[0333] The titled compound (75 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) and3-methyl-benzenemethanethiol (75 mg).

[0334] MS (APCI) 358 (M+H, 100%).

[0335]¹H NMR: δ(DMSO) 12.66 (1H, br s), 7.82 (1H, s), 7.73 (1H, br d),7.16-7.26 (3H, m), 7.05 (1H, br d), 4.82 (1H, br t), 4.34 (3H, m),3.40-3.54 (2H, m), 2.28 (3H, br d).

EXAMPLE 192-[(1,3-Benzodioxol-4-ylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethy]amino]-7(8H)-pteridinone

[0336] a) 1,3-Benzodioxole-4-methanethiol

[0337] The subtitled compound (0.29 g) was prepared by the method ofExample 6, step (c) using 4-(bromomethyl)-1,3-benzodioxole (0.51 g).

[0338] MS (EI) 168 (M+), 135 (100%).

[0339] b)2-[(1,3-Benzodioxol-4-ylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0340] The titled compound (57 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) andthe product from example 19, step (a) (0.10 g).

[0341] MS (APCI) 388 (M+H, 100%).

[0342]¹H NMR: δ(DMSO) 12.66 (1H, br s), 7.82 (1H, s), 7.75 (1H, br d),6.99 (1H, d), 6.80 (2H, m), 6.04 (2H, s), 4.82 (1H, t), 4.33 (3H, m),3.41-3.55 (2H, m), 1.16 (3H, d).

EXAMPLE 202-[[(2,4-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0343] a) 2,4-Difluoro-benzenemethanethiol

[0344] The subtitled compound (0.35 g) was prepared by the method ofExample 6, step (c) using 2,4-difluoro-benzyl bromide (0.55 g).

[0345] MS (EI) 160 (M+), 127 (100%).

[0346] b)2-[[(2,4-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0347] The titled compound (77 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) andthe product from example 20, step (a) (87 mg).

[0348] MS (APCI) 380 (M+H, 100%).

[0349]¹H NMR: δ(DMSO) 12.70 (1H, br), 7.83 (1H, s), 7.67-7.76 (2H, m),7.24 (1H, br t), 7.03 (1H, br t), 4.82 (1H, br), 4.30-4.37 (3H, m),3.43-3.49 (2H, m), 1.15 (3H, br d).

EXAMPLE 212-[[(3-Chlorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0350] The titled compound (66 mg) was prepared by the method of Example13, step (c) using the product from Example 13, step (a) (0.20 g) and3-chloro-benzenemethanethiol (92 mg).

[0351] MS (APCI) 378 (M+H, 100%).

[0352]¹H NMR: δ(DMSO) 12.70 (1H, br s), 7.82 (1H, s), 7.74 (1H, br d),7.55 (1H, s), 7.45 (1H), br d), 7.34 (2H, m), 4.81 (1H, br t), 4.31-4.43(3H, m), 3.43-3.50 (2H, m), 1.15 (3H, br d).

EXAMPLE 224-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone

[0353] The titled compound (0.038 g) was prepared by the method ofExample 13, step (c) using the product from Example 13, step (a) (0.10g) and 5-isoxazolylmethylmercaptan (0.057 g).

[0354] Mp 191-194° C.

[0355] MS (APCI) 335 (M+H, 100%).

[0356]¹H NMR: δ(DMSO) 12.71 (1H, br s), 8.47 (1H, s), 7.84 (1H, s), 7.80(1H, d), 6.51 (1H, s), 4.81 (1H, t), 4.54 (2H, q), 4.26 (1H, m), 3.44(2H, m), 1.13 (3H, d).

EXAMPLE 234-[[-2-Hydroxy-1-(hydroxymethylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone

[0357] a)2-[[(2,3-Difluorophenyl)methyl]sulfonyl]-4-[[-2-hydroxy-1-hydroxymethylethyl]amino]-7(8H)-pteridinone

[0358]2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[-2-hydroxy-1-hydroxymethylethyl]amino]-7(8H)-pteridinone(2.25 g) was stirred in acetonitrile (750 ml) and water (750 ml) withoxone (22.5 g) for 18 hrs. Acetonitrile was removed in vacuo to leave anaqueous suspension. The mixture was extracted into ethyl acetate. Thecombined extracts were washed with saturated sodium chloride solution,dried (MgSO₄) and the solvent removed in vacuo to afford the subtitledcompound (1.92 g).

[0359] MS (APCI) 428 (M+H)(100%)

[0360] b)4-[[-2-Hydroxy-1-(hydroxymethylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone

[0361] The titled compound (0.03 g) was prepared by the method ofExample 13, step (c) using the product from example 23, step (a) (0.20g) and 5-isoxazolylmethylmercaptan (0.1 g).

[0362] mp 199-203° C.

[0363] MS (APCI) 351 (M+H, 100%).

[0364]¹H NMR: δ(DMSO) 8.47(1H, s), 7.86 (1H, s), 7.54(1H , d), 6.55 (1H, s), 4.80 (2H, t), 4.56 (2H, s), 4.22 (1H, m), 3.55 (4H, m).

EXAMPLE 244-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(5-methyl-2-furanyl)methyl]thio]-7(8H)-pteridinone

[0365] The titled compound (0.058 g) was prepared by the method ofExample 13, step (c) using the product from Example 13, step (a) (0.20g) and 5-methyl-2-furanylmethylmercaptan (0.15 g of 80% pure).

[0366] Mp 197-199° C.

[0367] MS (APCI) 348 (M+H, 100%).

[0368]¹H NMR: δ(DMSO) 12.65 (1H, br s), 7.82 (1H, s), 7.74 (1H, d), 6.27(1H, d), 5.96 (1H, d), 4.83 (1H, t), 4.37 (2H, s), 4.32 (1H, m), 3.47(2H, m), 2.22 (3H, s), 1.17 (3H, d).

EXAMPLE 252-[[(2-Fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0369] The titled compound (0.089 g) was prepared by the method ofExample 13, step (c) using the product from Example 13, step (a) (0.20g) and 2-fluorobenzylmercaptan (0.083 g).

[0370] Mp 203-205° C.

[0371] MS (APCI) 362 (M+H, 100%).

[0372]¹H NMR: δ(DMSO) 12.69 (11H, br s), 7.83 (1H, s), 7.75 (1H, d),7.64 (1H, m), 7.32 (1H, m), 7.20 (1H, m), 7.14 (1H, m), 4.82 (1H, t),4.41 (2H, q), 4.31 (1H, m), 3.47 (2H, m) 1.15 (3H, d).

EXAMPLE 264-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(2-thienyl)methyl)thio]-7(8H)-pteridinone

[0373] The titled compound (0.076 g) was prepared by the method ofExample 13, step (c) using the product from Example 13, step (a) (0.20g) and 2-thienylmethylmercaptan (0.050 g).

[0374] Mp 209-212° C.

[0375] MS (APCI) 350 (M+H, 100%).

[0376]¹H NMR: δ(DMSO) 12.66 (1H, br s), 7.83 (1H, s), 7.77 (1H, d), 7.37(1H, d), 7.12 (1H, d), 6.93 (1H, dd), 4.82 (1H, t), 4.62 (2H, q), 4.36(1H, m), 3.46 (2H, m), 1.17 (3H, d).

EXAMPLE 272-[[(2-Fluorophenyl)methyl]thio]-4-[[-2-hydroxy-1-(hydroxymethylethyl]amino]-7(8H)-pteridinone

[0377] The titled compound (0.088 g) was prepared by the method ofExample 13, step (c) using the product from example 23 step (a) (0.21 g)and 2-fluorobezylmercaptan (0.83 g).

[0378] mp 206-208° C.

[0379] MS (APCI) 378 (M+H, 100%).

[0380]¹H NMR: δ(DMSO) 12.67 (1H,br s), 7.84 (1H, s), 7.66 (1H, t), 7.47(1H, d), 7.32 (1H, m), 7.16 (2H, m), 4.80 (2H, t), 4.41 (2H, s), 4.25(1H, m), 3.57 (4H, m).

EXAMPLE 284-[[-2-Hydroxy-1-(hydroxymethyl)ethyl]amino]-2-[(2-thienylmethyl)thio]-7(8H)-pteridinone

[0381] The titled compound (0.075 g) was prepared by the method ofExample 13, step (c) using the product from example 23, step (a) (0.21g) and 2-thienylmethylmercaptan (0.05 g).

[0382] mp 220-223° C.

[0383] MS (APCI) 366 (M+H, 100%).

[0384]¹H NMR: δ(DMSO) 12.67 (1H,br s), 7.85 (1H, s), 7.49 (1H, d), 7.38(1H, d), 7.15 (1H, d), 6.93 (1H, dd), 4.81 (2H, t), 4.64 (2H, s), 4.28(1H, m), 3.59 (4H, m).

EXAMPLE 292-[[(2-Fluoro-5-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0385] a) 2-Fluoro-5-methyl-benzenemethanethiol, acetate

[0386] Diisopropylazodicarboxylate (2.68 ml) was added to a solution oftriphenylphosphine (3.57 g) in dry THF (30 ml) at 0° C. The mixture wasstirred for 1 hr. A solution of 2-fluoro-5-methyl-benzenemethanol (0.96ml) in dry THF (10 ml) was added dropwise over 40 mins. The mixture wasstirred for 1 hr then warmed to room temp and stirred for a further 3hrs. The solvent was evaporated and the residue slurried with ether andfiltered. The filtrate was evaporated and purified by columnchromatography, eluting with 3% ethyl acetate in isohexane to give thesubtitled compound as an oil (1.23 g).

[0387] GC/MS 100% (EI) 198 (M+), 123 (100%)

[0388] b) 2-Fluoro-5-methyl-benzylmethanethiol

[0389] 2-Fluoro-5-methyl-benzenemethanethiol acetate (1.2 g) was stirredin methanol previously saturated with ammonia (10 ml) at room temp for30 mins. The solvent was evaporated and the residue partitioned betweenether and water. The layers were separated and the water extracted withether. The combined ether was washed with water, dried and evaporated toleave an oil (0.9 g).

[0390] GC/MS 97% (EI) 156(M+) 123(100%)

[0391] (c)2-[[(2-Fluoro-5-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0392] The titled compound (0.093 g) was prepared by the method ofExample 13, step (c) using the product from Example 13, step (a) (0.20g) and the product from example 29, step (b).

[0393] Mp 202-204° C.

[0394] MS (APCI) 376 (M+H, 100%).

[0395]¹H NMR: δ(DMSO) 12.68 (1H, br s), 7.82 (1H, s), 7.74 (1H, d), 7.41(1H, d), 7.07 (2H, m), 4.83 (1H, t), 4.33 (3H, m), 3.49 (2H, m), 2.25(3H, s), 1.17 (3H, d).

EXAMPLE 302-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0396] a)4-(1-Methylethoxy)-2-[[[3-(trifluoromethyl)phenyl]methyl]thio]-7(8H)-pteridinone

[0397]6-[[[2-Fluoro-3-(trifluoromethyl)phenyl]methyl]thio]-2-[[[3-(trifluoromethyl)phenyl]methyl]thio]-4,5-pyrimidinediamine(7.12 g) was added to a solution of sodium methoxide prepared fromsodium (0.62 g) and methanol (150 ml). Ethyl glyoxalate (6.5 ml of 50%in toluene) was added and the mixture heated under reflux for 30 mins.The solvent was evaporated and redisolved in 2-propanol. Sodium (1.1 g)was added and the mixture heated under reflux for 30 mins. The solventwas evaporated and the residue taken up in water and acidified withdilute hydrochloric acid. The mixture was extracted with dichloromethaneand the extracts washed with water then dried (MgSO₄), and evaporated.Purification by flash chromatography eluting with 10% ethyl acetate indichloromethane to give the subtitled compound as an solid (2.64 g).

[0398] mp 205-206° C.

[0399] MS (APCI) 415(M+H, 100%)

[0400]¹H NMR: δ(DMSO) 13.03 (1H, s), 8.06 (1H, t), 7.97 (1H, s), 7.70(1H, t), 7.38 (1H, t), 5.38 (1H, m), 4.53 (2H, s), 1.31 (6H, d).

[0401] b)2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone

[0402] The product from example 30, step (a) (0.3 g) and D-alaninol (0.6ml) were sonicated with N-methylimidazole (1 ml) to form a paste. Thepaste was heated in a 300W microwave at 160° C. for 25 mins. Solvent wasremoved by bulb to bulb distillation and the residue purified by reversephase HPLC to give the title compound (0.52 g).

[0403] Mp 217-219° C.

[0404] MS (APCI) 430 (M+H, 100%)

[0405]¹H NMR: δ(DMSO) 8.03 (1H, t), 7.83 (1H, s), 7.76 (1H, d), 7.68(1H, t), 7.35 (1H, t) 4.82 (1H, t), 4.47 (2H, q), 4.26 (1H, m), 3.45(2H, m), 1.12 (3H, d).

EXAMPLE 312-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone

[0406] The titled compound (0.049 g) was prepared by the method ofExample 30, step (b) using the product from Example 30, step (a) (0.30g) and 2-aminopropane-1,3-diol (0.66 g).

[0407] Mp 244-245° C.

[0408] MS (APCI) 446 (M+H, 100%).

[0409]¹H NMR: δ(DMSO) 12.76 (1H, s), 8.06 (1H, t), 7.85 (1H, s), 7.68(1H, t), 7.52 (1H, d), 7.35 (1H, t), 4.81 (2H, t), 4.47 (2H, s), 4.23(1H, m), 3.55 (4H, m).

EXAMPLE 32

[0410]2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0411] The titled compound (0.072 g) was prepared by the method ofExample 30, step (b) using the product from Example 30, step (a) (0.30g) and ethanolamine (0.5 ml)

[0412] Mp 221-222° C.

[0413] MS (APCI) 416 (M+H, 100%).

[0414]¹H NMR: δ(DMSO) 12.73 (1H, s), 8.08 (1H, m), 7.03 (1H, t), 7.85(1H, s), 7.68 (1H, t), 7.36 (1H, t), 4.78 (1H, t), 4.47 (2H, s), 3.52(4H, m).

EXAMPLE 334-[(2-aminoethyl)amino]-2-[[(2-fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-7(8H)-pteridinone

[0415] The titled compound (0.054 g) was prepared by the method ofExample 30, step (b) using the product from Example 30, step (a) (0.30g) and ethylenediamine (0.5 ml). The product was purified bycrystallisation from methanol.

[0416] MS (APCI) 415 (M+H, 100%).

[0417]¹H NMR: δ(DMSO) 8.01 (1H, t), 7.91 (1H, br s), 7.67 (1H, m), 7.58(1H, br s), 7.52 (1H, bs), 7.35 (1H, t), 7.17 (1H, br s), 4.45 (2H, s),3.42 (2H,t), 3.15 (2H, br s), 2.75 (8H, m).

EXAMPLE 342-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-7(8H)-pteridinone

[0418] The product of example 2, step (e) (400 mg) was dissolved inN-methylpyrrolidinone (15 ml), and Hunigs base (0.36 ml) was addedfollowed by 2-amino-2-methyl-1,3-propanediol (0.273 g). The mixture wasstirred at 1 10° C. for 17 hours. The resulting mixture was poured in towater, and allowed to stand overnight to allow a solid to precipitateout. This solid was collected by filtration, then purified by reversephase preparative HPLC on symmetry C-8®, using 10 to 95% acetonitrile in0.1% aqueous ammonium acetate at 20 ml/min over 10 min to give the titlecompound as off white needles (0.113 g).

[0419] MS: APCI (+ve) 410 (M+H)

[0420]¹H NMR: δ(DMSO) 1.30 (3H, s), 3.54-3.58 (2H, m), 3.63-3.67 (2H,m), 4.45 (2H, s) 4.98-5.01 (2H, t), 7.13 (1H, s), 7.15-7.19 (1H, m),7.31-7.36 (1H, m), 7.45-7.49 (1H, t), 7.84 (1H, s), 12.74 (1H, bs).

EXAMPLE 352-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methyl-7(8H)-pteridinone

[0421] a)4-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-6-methyl-7(8H)-pteridinone

[0422] The sub-titled compound was prepared from the product of Example2, step (b) (2 g) and triethylphosphonopropionate (3.2 g) using themethod of Example 3, step (a).

[0423] MS: APCI (+ve) 336 (M+1)

[0424]¹H NMR: δ(DMSO) 2.33 (s,3H), 4.40 (s,2H), 7.09-7.58 (m,3H), 12.56(bs,1H).

[0425] b)4-Bromo-2-[[(2,3-difluorophenyl)methyl]thio]-6-methyl-7(8H)-pteridinone

[0426] The sub-titled compound was prepared from the product of example35, step (a) (1.5 g) and bromoform (30 ml) using the method of Example3, step (b).

[0427] MS: APCI (+ve) 400 (M+1)

[0428]¹H NMR: δ(DMSO) 2.39 (s,3H), 4.52 (s,2H), 7.11-7.55 (m,3H), 13.21(bs,1H).

[0429] c)2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methyl-7(8H)-pteridinone

[0430] The titled compound was prepared from the product of example 35,step (b) (200 mg) and D-alaninol (120 μl) using the method of Example 2,step (f).

[0431] MS: APCI (+ve) 394 (M+1)

[0432]¹H NMR: δ(DMSO) 1.12 (d,3H), 2.34 (s,3H), 3.45 (m,2H,), 4.24 4.33(m,1H), 4.43 (s,2H), 4.85 (bs,1H), 7.10-7.49 (m,3H), 12.58 (s,1H).

EXAMPLE 362-[[(2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7-oxo-6-pteridinecarboxylicacid ethyl ester

[0433] a)4-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-6-pteridinecarboxylicacid ethyl ester

[0434] The product of Example 2, step (b) (5 g) was dissolved in diethylmalonate (100 ml) and heated to 120° C. for 10 hr, with stirring. Thereaction mixture was allowed to cool and the solid that precipitated wasfiltered, washed with water and dried in the oven at 50° C. to yield theproduct as a yellow solid (3.2 g).

[0435] MS: APCI (+ve) 394 (M+1)

[0436]¹H NMR: δ(DMSO) 1.29-1.33 (t,3H), 4.28-4.35 (q,2H), 4.42 (s,2H)7.11-7.59 (m,3H), 7.88 (bs,1H), 8.08 (bs,1H), 13.05 (s,1H).

[0437] b)4-Bromo-2-[[(2,3-difluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-6-pteridinecarboxylicacid ethyl ester

[0438] The sub-titled compound was prepared from the product of example36, step (a) (2 g) and bromoform (40 ml) using the method of Example 3,step (b).

[0439] MS: APCI (+ve) 458 (M+1)

[0440]¹H NMR: δ(DMSO) 1.31 (t,3H), 4.40 (q,2H), 4.52 (s,2H), 7.13-7.55(m,3H), 13.05 (s,1H).

[0441] c)2-[[(2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7-ox-6-pteridinecarboxylicacid ethyl ester

[0442] The titled compound was prepared from the product of example 36,step (b) (300 mg) and D-alaninol (180 μl) using the method of Example 2,step (f).

[0443] MS: APCI (+ve) 451 (M+1)

[0444]¹H NMR: δ(DMSO) 1.12 (d,3H), 1.29 (t,3H), 3.41-3.53 (m,2H),4.22-4.32 (m,3H), 4.51 (s,2H), 4.83-4.86 (t,1H), 7.07-7.47 (m,3H).

EXAMPLE 372-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(trifluoromethyl)-7(8H)-pteridinone

[0445] a)4-Amino-2-[[(2,3-difluorophenyl)methyl]thio]-6-(trifluoromethyl)-7(8H)-pteridinone

[0446] The sub-titled compound was prepared from the product of Example2, step (c) (5 g) and trifluoropyruvate (10 ml) using the method ofExample 2, step (d).

[0447] MS: APCI (+ve) 390 (M+1)

[0448]¹H NMR: δ(DMSO) 4.32 (s,2H), 7.10-7.70 (m,3H), 7.92-8.23 (2bs,2H),13.23 (bs,1H)

[0449] b)4-Bromo-2-[[(2,3-difluorophenyl)methyl]thio]-6-(trifluoromethyl)-7(8H)-pteridinone

[0450] The sub-titled compound was prepared from the product of example37, step (a) (1.5 g) and bromoform (30 ml) using the method of Example3, step (b).

[0451] MS: APCI (+ve) 454 (M+1).

[0452] c)2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(trifluoromethyl)-7(8,H)-pteridinone

[0453] The titled compound was prepared from the product of example 37,step (b) (150 mg) and D-alaninol (100 μl) using the method of Example 2,step (f).

[0454] MS: APCI (+ve) 448 (M+1)

[0455]¹H NMR: δ(DMSO) 1.15 (d,3H), 3.50 (m,2H), 4.37 (m,1H), 4.47(s,2H), 4.89 (t,1H), 7.12-7.49 (m,3H), 7.79 (d,1H), 13.25 (bs,1H).

EXAMPLE 382-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinonesodium salt

[0456] The product from example 2, step (f) was suspended in watercontaining one equivalent of sodium hydroxide, followed by the additionof a small aliquot of tetrahydrofuiran and methanol to aid dissolution.The resultant solution was then lyopholised to give the title compoundas a colourless solid.

[0457] m.p. 255-260° C. (dec)

[0458] MS: APCI (+ve) 380 (M+1)

[0459]¹H NMR: δ(DMSO) 7.42 (1H, m), 7.37 (1H, s), 7.31 (1H, m), 7.13(1H, m), 6.89 (1H, d), 4.79 (1H, t), 4.40 (2H, s), 4.15 (1H, m), 3.45(2H, m), 1.12 (3H, d).

EXAMPLES 39-72

[0460] Examples 39 to 72 were prepared by heating the product of example2, step (e) (2.5×10⁻⁶ moles) with the appropriate amine (2 equivalents)and N-ethyldiisopropylamine (6 equivalents) in N-methylpyrrolidinone(0.25 ml) in a sealed vessel at 100° C. for 1 hour.

EXAMPLE 39 2-[(2,3-difluorobenzyl)thio]-4-(ethylamino)-7(8H)-pteridinone

[0461] MS: APCI (+ve) 350 (M+1).

EXAMPLE 402-[(2,3-difluorobenzyl)thio]-4-(isopropylamino)-7(8H)-pteridinone

[0462] MS: APCI (+ve) 364 (M+1).

EXAMPLE 41(+/−)-4-(see-butylamino)-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0463] MS: APCI (+ve) 378 (M+1).

EXAMPLE 422-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)acetamide

[0464] MS: APCI (+ve) 379 (M+1).

EXAMPLE 43(+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]-7(8H)-pteridinone

[0465] MS: APCI (+ve) 380 (M+1).

EXAMPLE 44(S)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone

[0466] MS: APCI (+ve) 380 (M+1).

EXAMPLE 45(+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone

[0467] MS: APCI (+ve) 380 (M+1).

EXAMPLE 46(R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]-7(8H)-pteridinone

[0468] MS: APCI (+ve) 380 (M+1).

EXAMPLE 472-[(2,3-difluorobenzyl)thio]-4-[(3-hydroxypropyl)amino]-7(8H)-pteridinone

[0469] MS: APCI (+ve) 380 (M+1).

EXAMPLE 482-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxyethyl)(methyl)amino]-7(8H)-pteridinone

[0470] MS: APCI (+ve) 380 (M+1).

EXAMPLE 493-[{2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}(methyl)amino]propanenitrile

[0471] MS: APCI (+ve) 389 (M+1).

EXAMPLE 50(R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8m)-pteridinone

[0472] MS: APCI (+ve) 394 (M+1).

EXAMPLE 51(S)-2-[(2,3-difluorobenzyl)thio]4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0473] MS: APCI (+ve) 394 (M+1).

EXAMPLE 522-[(2,3-difluorobenzyl)thio]-4-[(4-hydroxybutyl)amino]-7(8H)-pteridinone

[0474] MS: APCI (+ve) 394 (M+1).

EXAMPLE 53(+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0475] MS: APCI (+ve) 394 (M+1).

EXAMPLE 542-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1,1-dimethylethyl)amino]-7(8H)-pteridinone

[0476] MS: APCI (+ve) 394 (M+1).

EXAMPLE 552-[(2,3-difluorobenzyl)thio]-4-[ethyl(2-hydroxyethyl)amino]-7(8H)-pteridinone

[0477] MS: APCI (+ve) 394 (M+1).

EXAMPLE 56(+/−)-4-[(3-amino-2-hydroxypropyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0478] MS: APCI (+ve) 395 (M+1).

EXAMPLE 57(+/−)-2-[(2,3-difuorobenzyl)thio]-4-[(1,3-dimethylbutyl)amino]-7(8H)-pteridinone

[0479] MS: APCI (+ve) 406 (M+1).

EXAMPLE 58(1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxycyclopentyl)amino]-7(8H)-pteridinone

[0480] MS: APCI (+ve) 406 (M+1).

EXAMPLE 592-[(2,3-difluorobenzyl)thio]-4-[(5-hydroxypentyl)amino]-7(8H)-pteridinone

[0481] MS: APCI (+ve) 408 (M+1).

EXAMPLE 60(+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)butyl]amino}-7(8H)-pteridinone

[0482] MS: APCI (+ve) 408 (M+1).

EXAMPLE 61 (+/−)-methyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)propanoate

[0483] MS: APCI (+ve) 408 (M+1).

EXAMPLE 622-[(2,3-difuorobenzyl)thio]-4-[(3-hydroxy-2,2-dimethylpropyl)amino]-7(8H)-pteridinone

[0484] MS: APCI (+ve) 408 (M+1).

EXAMPLE 63(1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-{[2-hydroxy-1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone

[0485] MS: APCI (+ve) 410 (M+1).

EXAMPLE 644-[bis(2-hydroxyethyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0486] MS: APCI (+ve) 410 (M+1).

EXAMPLE 652-[(2,3-difluorobenzyl)thio]4-{[2-(2-hydroxyethoxy)ethyl]amino}-7(8H)-pteridinone

[0487] MS: APCI (+ve) 410 (M+1).

EXAMPLE 662-[(2,3-difluorobenzyl)thio]-4-[(2,2-dimethoxyethyl)amino]-7(8H)-pteridinone

[0488] MS: APCI (+ve) 410 (M+1).

EXAMPLE 674-{[2-(diethylamino)ethyl]amino}-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone

[0489] MS: APCI (+ve) 421 (M+1).

EXAMPLE 68(S)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)-2,2-dimethylpropyl]amino}-7(8H)-pteridinone

[0490] MS: APCI (+ve) 422 (M+1).

EXAMPLE 69(R)-2-[(2,3-difluorobenzvl)thio]-4-{[1-(hydroxymethyl)-3-methylbutyl]amino}-7(8H)-pteridinone

[0491] MS: APCI (+ve) 422 (M+1).

EXAMPLE 702-[(2,3-difluorobenzyl)thio]-4-[(6-hydroxyhexyl)amino]-7(8H)-pteridinone

[0492] MS: APCI (+ve) 422 (M+1).

EXAMPLE 712-[(2,3-difluorobenzyl)thio]-4-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-7(8H)-pteridinone

[0493] MS: APCI (+ve) 436 (M+1).

EXAMPLE 72 (S)-ethyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)-3-hydroxypropanoate

[0494] MS: APCI (+ve) 438 (M+1).

[0495] Pharmacological Data

[0496] Ligand Binding Assay

[0497] [¹²⁵I]IL-8 (human, recombinant) was purchased from Amersham, U.K.with a specific activity of 2,000 Ci/mmol. All other chemicals were ofanalytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells(human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. (1992) J.Biol. Chem. 267 pp16283-16291). hrCXCR2 cDNA was amplified and clonedfrom human neutrophil mRNA. The DNA was cloned into PCRScript(Stratagene) and clones were identified using DNA. The coding sequencewas sub-cloned into the eukaryotic expression vector RcCMV (Invitrogen).Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfectedinto HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of thehighest expressing clone were harvested in phosphate-buffered salinecontaining 0.2% (w/v) ethylenediaminetetraacetic acid (EDTA) andcentrifuged (200 g, 5 min.). The cell pellet was resuspended in ice coldhomogenisation buffer [10 mM HEPES (pH 7.4), 1 mM dithiothreitol, 1 mMEDTA and a panel of protease inhibitors (1 mM phenyl methyl sulphonylfluoride, 2μg/ml soybean trypsin inhibitor, 3 mM benzamidine, 0.5 μl/mlleupeptin and 100 μg/ml bacitracin)] and the cells left to swell for 10minutes. The cell preparation was disrupted using a hand held glassmortar/PTFE pestle homogeniser and cell membranes harvested bycentrifuigation (45 minutes, 100,000 g, 4° C.). The membrane preparationwas stored at −70° C. in homogenisation buffer supplemented withTyrode's salt solution (137 mM NaCl, 2.7mM KCl, 0.4 mM NaH₂PO₄), 0.1%(w/v) gelatin and 10% (v/v) glycerol.

[0498] All assays were performed in a 96-well MultiScreen 0.45 μmfiltration plates (Millipore, U.K.). Each assay contained ˜50 pM[¹²⁵I]IL-8 and membranes (equivalent to ˜200,000 cells) in assay buffer[Tyrode's salt solution supplemented with 10 mM HEPES (pH 7.4), 1.8 mMCaCl₂, 1 mM MgCl₂, 0.125 mg/ml bacitracin and 0.1% (w/v) gelatin]. Inaddition, a compound of formula (I) according to the Examples waspre-dissolved in DMSO and added to reach a final concentration of 1%(v/v) DMSO. The assay was initiated with the addition of membranes andafter 1.5 hours at room temperature the membranes were harvested byfiltration using a Millipore MultiScreen vacuum manifold and washedtwice with assay buffer (without bacitracin). The backing plate wasremoved from the MultiScreen plate assembly, the filters dried at roomtemperature, punched out and then counted on a Cobra γ-counter.

[0499] The compounds of formula (I) according to the Examples were foundto have IC₅₀ values of less than (<) 10 μM.

[0500] Intracellular Calcium Mobilisation Assay

[0501] Human neutrophils were prepared from EDTA-treated peripheralblood, as previously described (Baly et al. (1997) Methods in Enzymology287 pp70-72), in storage buffer [Tyrode's salt solution (137 mM NaCl,2.7 mM KCl, 0.4 mM NaH₂PO₄) supplemented with 5.7 mM glucose and 10 mMHEPES (pH 7.4)].

[0502] The chemokine GROα (human, recombinant) was purchased from R&DSystems (Abingdon, U.K.). All other chemicals were of analytical grade.Changes in intracellular free calcium were measured fluorometrically byloading neutrophils with the calcium sensitive fluorescent dye, fluo-3,as described previously (Merritt et al. (1990) Biochem. J. 269,pp513-519). Cells were loaded for 1 hour at 37° C. in loading buffer(storage buffer with 0.1% (w/v) gelatin) containing 5 μM fluo-3 AMester, washed with loading buffer and then resuspended in Tyrode's saltsolution supplemented with 5.7 mM glucose, 0.1% (w/v) bovine serumalbumin (BSA), 1.8 mM CaCl₂ and 1 mM MgCl₂. The cells were pipetted intoblack walled, clear bottom, 96 well micro plates (Costar, Boston,U.S.A.) and centrifuged (200 g, 5 minutes, room temperature).

[0503] A compound of formula (I) according to the Examples waspre-dissolved in DMSO and added to a final concentration of 0.1% (v/v)DMSO. Assays were initiated by the addition of an Aso concentration ofGROα and the transient increase in fluo-3 fluorescence (λ_(Ex)=490 nmand λ_(Em) =520 nm) monitored using a FLIPR (Fluorometric Imaging PlateReader, Molecular Devices, Sunnyvale, U.S.A.).

[0504] The compounds of formula (I) according to the Examples weretested and found to be antagonists of the CXCR2 receptor in humanneutrophils.

1. A compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

in which: A is a group of formula (a) or (b):

R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, the latter four groups being optionally substituted byone or more substituent groups independently selected from halogenatoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, an aryl or heteroaryl group both of which can beoptionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl ortrifluoromethyl groups; one of R² and R³ is hydrogen and the other isC₃-C₄ alkyl substituted by one or more hydroxy groups; R⁴ representshydrogen, C₁-C₆ alkyl or a phenyl group the latter two of which may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR¹¹ and —NR¹²R¹³; R⁵ and R⁶independently represent a hydrogen atom or a C₁-C₆ alkyl or phenyl groupthe latter two of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ orR⁵ and R⁶ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocyclic ring system optionallycomprising a further heteroatom selected from oxygen and nitrogen atoms,which ring system may be optionally substituted by one or moresubstituent groups independently selected from phenyl, —OR¹⁴, —COOR¹⁴,—NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆alkyl, itself optionally substituted by one or more substituentsindependently selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;R¹⁰ represents a C₁-C₆ alkyl or a phenyl group, each of which may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; X is O, S orNR⁸; Y is CR¹⁸R¹⁹; Z is CR²⁰ where R²⁰ represents a C₁-C₆ alkyl or aphenyl group, each of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR²¹ and —NR²²R²³, or an acyl group selected from CO₂R²¹ or CONR²²R²³;and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²¹, R²² and R²³ independently represent a hydrogen atom, C₁-C₆, alkyl,or a phenyl group.
 2. A compound according to claim 1, wherein R¹represents an optionally substituted benzyl group.
 3. A compoundaccording to claim 1 or claim 2, wherein one of R² and R³ is hydrogenand the other is C₃-C₄ alkyl substituted by one or more hydroxy groups.4. A compound according to any one of claims 1 to 3 wherein one of R²and R³ is hydrogen and the other is CH(CH₃)CH₂OH, CH(Et)CH₂OH,C(CH₃)₂CH₂OH or CH(CH₂OH)₂.
 5. A compound according to any one of claims1 to 3 wherein one of R² and R³ is hydrogen and the other isCH(CH₃)CH₂OH.
 6. A compound according to any one of claims 3 to 5 in theform of the (R) isomer.
 7. A compound according to any one of claims 1to 6 wherein A is a group of formula (b) and Z═CR²⁰.
 8. A compoundaccording to claim 7 wherein R²⁰ is hydrogen.
 9. A compound according toclaim 1 selected from:4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(phenylmethyl)thio]-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone(2R)-2-[[2-[[2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]-propanamide2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone[(2R)-2-[[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-7,8-dihydro-7-oxo-4-pteridinyl]amino]propyl]-carbamicacid, 1,1-dimethylethyl ester4-[[(1R)-2-Amino-1-methylethyl]amino]-2-[[(3-chloro-2-fluorophenyl)methyl]thio]-7(8H)-pteridinone,monohydrochloride2-[[(3-Chloro-4-methoxyphenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone4-[(2-Aminoethyl)amino]-2-[[(3-chloro-4-methoxyphenyl)methyl]thio]-7(8H)-pteridinone,monotrifluoroacetate2-[[(2-Fluoro-4-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2-Fluoro-3-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(3-Fluoro-2-methoxyphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8h)-pteridinone2-[[[4-(Difluoromethoxy)phenyl]methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(4-hydroxyphenyl)methyl]thio]-7(8H)-pteridinone4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(3-methylphenyl)methyl]thio]-7(8H)-pteridinone2-[(1,3-Benzodioxol-4-ylmethyl)thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2,4-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(3-Chlorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinoe4-[[-2-Hydroxy-1-(hydroxymethylethyl]amino]-2-[(5-isoxazolylmethyl)thio]-7(8H)-pteridinone4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(5-methyl-2-furanyl)methyl]thio]-7(8H)-pteridinone2-[[(2-Fluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone4-[[(1R)-2-Hydroxy-1-methylethyl]amino]-2-[[(2-thienyl)methyl)thio]-7(8H)-pteridinone2-[[(2-Fluorophenyl)methyl]thio]-4-[[-2-hydroxy-1-(hydroxymethylethyl]amino]-7(8H)-pteridinone4-[[-2-Hydroxy-1-(hydroxymethyl)ethyl]amino]-2-[(2-thienylmethyl)thio]-7(8H)-pteridinone2-[[(2-Fluoro-5-methylphenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-7(8H)-pteridinone2-[[(2-Fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-4-[(2-hydroxyethyl)amino]-7(8H)-pteridinone4-[(2-aminoethyl)amino]-2-[[(2-fluoro-3-(trifluoromethyl)phenyl)methyl]thio]-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-methyl-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-7,8-dihydro-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7-oxo-6-pteridinecarboxylicacid ethyl ester2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-6-(trifluoromethyl)-7(8H)-pteridinone2-[[(2,3-Difluorophenyl)methyl]thio]-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinonesodium salt2-[(2,3-difluorobenzyl)thio]-4-(ethylamino)-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-(isopropylamino)-7(8H)-pteridinone(+/−)-4-(sec-butylamino)-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)acetamide(+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]-7(8H)-pteridinone(S)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone(+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1-methylethyl)amino]-7(8H)-pteridinone(R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxypropyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(3-hydroxypropyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxyethyl)(methyl)amino]-7(8H)-pteridinone3-[{2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}(methyl)amino]propanenitrile(R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone(R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(4-hydroxybutyl)amino]-7(8H)-pteridinone(+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxy-1,1-dimethylethyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[ethyl(2-hydroxyethyl)amino]-7(8H)-pteridinone(+/−)-4-[(3-amino-2-hydroxypropyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone(+/−)-2-[(2,3-difluorobenzyl)thio]-4-[(1,3-dimethylbutyl)amino]-7(8H)-pteridinone(1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-[(2-hydroxycyclopentyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(5-hydroxypentyl)amino]-7(8H)-pteridinone(+/−)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)butyl]amino}-7(8H)-pteridinone(+/−)-methyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)propanoate2-[(2,3-difluorobenzyl)thio]-4-[(3-hydroxy-2,2-dimethylpropyl)amino]-7(8H)-pteridinone(1R,2R)-2-[(2,3-difluorobenzyl)thio]-4-{[2-hydroxy-1-(hydroxymethyl)propyl]amino}-7(8H)-pteridinone4-[bis(2-hydroxyethyl)amino]-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-{[2-(2-hydroxyethoxy)ethyl]amino}-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-[(2,2-dimethoxyethyl)amino]-7(8H)-pteridinone4-{[2-(diethylamino)ethyl]amino}-2-[(2,3-difluorobenzyl)thio]-7(8H)-pteridinone(S)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)-2,2-dimethylpropyl]amino}-7(8H)-pteridinone(R)-2-[(2,3-difluorobenzyl)thio]-4-{[1-(hydroxymethyl)-3-methylbutyl]amino}-7(8H)-ptenridinone2-[(2,3-difluorobenzyl)thio]-4-[(6-hydroxyhexyl)amino]-7(8H)-pteridinone2-[(2,3-difluorobenzyl)thio]-4-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-7(8H)-pteridinone(S)-ethyl2-({2-[(2,3-difluorobenzyl)thio]-7-oxo-7,8-dihydro-4-pteridinyl}amino)-3-hydroxypropanoateand their pharmaceutically acceptable salts and solvates.
 10. A processfor the preparation of a compound of formula (I) as defined in claim 1which comprises: (a) treatment of a compound of formula (IIA):

 where R¹ is as defined in formula (I) or is a protected derivativethereof and L is a leaving group with an amine HNR²R³, or (b) treatmentof a compound of formula (IIB):

 where R¹ is as defined in formula (I) or is a protected derivativethereof and L is a leaving group with an amine HNR²R³, or (c) treatmentof a compound of formula (IIC):

 where R¹, R² and R³ are as defined in formula (I) or are protectedderivatives thereof with a thiol R¹SH, or (d) treatment of a compound offormula (IID):

 where R¹ is as defined in formula (I) or is a protected derivativethereof and L′ is a leaving group with an amine HNR²R³, and optionallythereafter process (a), (b), (c) or (d) and in any order: removing anyprotecting groups forming a pharmaceutically acceptable salt.
 11. Anintermediate compound of formula (IIA) or (IIB) or (IIC) or (IID) asdefined in claim
 10. 12. A pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in any one of claims 1 to 9 in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.
 13. Aprocess for the preparation of a pharmaceutical composition as claimedin claim 12 which comprises mixing a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 9 with a pharmaceutically acceptable adjuvant,diluent or carrier.
 14. A compound of formula (I), or apharmaceutically-acceptable salt or solvate thereof, as claimed in anyone of claims 1 to 9 for use in therapy.
 15. Use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,as claimed in any one of claims 1 to 9 in the manufacture of amedicament for use in therapy.
 16. A method of treating a chemokinemediated disease wherein the chemokine binds to one or more chemokinereceptors, which comprises administering to a patient a therapeuticallyeffective amount of a compound of formula (IA), or a pharmaceuticallyacceptable salt or solvate thereof.

in which: A is a group of formula (a) or (b):

R¹ represents a C₃-C₇ carbocyclic, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl group, the latter four groups being optionally substituted byone or more substituent groups independently selected from halogenatoms, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰,—SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, an aryl or heteroaryl group both of which can beoptionally substituted by one or more substituents independentlyselected from halogen atoms, cyano, nitro, —OR⁴, —NR⁵R⁶, —CONR⁵R⁶,—COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶, —NR⁸SO₂R¹⁰, C₁-C₆ alkyl ortrifluoromethyl groups; R² represents hydrogen or a C₃-C₇ carbocyclicgroup, C₁-C₈ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl group, the latterfour groups may be optionally substituted by one or more substituentgroups independently selected from halogen atoms, —OR⁴, —NR⁵R⁶ —CONR⁵R⁶,—COOR⁷, —NR⁸COR⁹, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶ or —NR⁸SO₂R⁹; R³ representshydrogen or C₂-C₆ alkyl optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁰ and —NR¹¹R¹²; or R² and R³ represent a 3-8 membered ringoptionally containing one or more atoms selected from O, S, NR⁸ anditself optionally substituted by C₁₋₃-alkyl, halogen or OR⁴; R⁴represents hydrogen, C₁-C₆ alkyl or a phenyl group the latter two ofwhich may be optionally substituted by one or more substituent groupsindependently selected from halogen atoms, phenyl, —OR¹¹ and —NR¹²R¹³;R⁵ and R⁶ independently represent a hydrogen atom or a C₁-C₆ alkyl orphenyl group the latter two of which may be optionally substituted byone or more substituent groups independently selected from halogenatoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂NR¹⁵R¹⁶,NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom to which theyare attached form a 4- to 7-membered saturated heterocyclic ring systemoptionally comprising a further heteroatom selected from oxygen andnitrogen atoms, which ring system may be optionally substituted by oneor more substituent groups independently selected from phenyl, —OR¹⁴,—COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶, —SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ orC₁-C₆ alkyl, itself optionally substituted by one or more substituentsindependently selected from halogen atoms and —NR¹⁵R¹⁶ and —OR¹⁷ groups;R¹⁰ represents a C₁-C₆ alkyl or a phenyl group, each of which may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR¹⁷ and —NR¹⁵R¹⁶; X is O, S orNR⁸; Y is CR¹⁸R¹⁹; Z is CR²⁰ where R²⁰ represents a C₁-C₆ alkyl or aphenyl group, each of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR²¹ and —NR²²R²³, or an acyl group selected from CO₂R²¹ or CONR²²R²³;and each of R⁷, R⁸, R⁹, R¹¹, R¹², R¹³, R¹⁴ R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹,R²² and R²³ independently represent a hydrogen atom, C₁-C₆, alkyl, or aphenyl group.
 17. A method according to claim 16 in which the chemokinereceptor belongs to the CXC chemokine receptor subfamily.
 18. A methodaccording to claim 16 or 17 in which the chemokine receptor is the CXCR2receptor.
 19. A method of treating an inflammatory disease in a patientsuffering from, or at risk of, said disease, which comprisesadministering to the patient a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as claimed in any one of claims 1 to
 9. 20. A methodaccording to claim 19, wherein the disease is psoriasis, a disease inwhich angiogenesis is associated with raised CXCR2 chemokine levels, orCOPD.
 21. A method according to claim 19, wherein the disease ispsoriasis.
 22. Use of a compound of formula (IA):

in which: A is a group of formula (a) or (b):

R¹ represents benzyl optionally substituted by one or more substituentgroups independently selected from halogen atoms, cyano, nitro, —OR⁴,—NR⁵R⁶, —CONR⁵R⁶, —COOR⁷, —NR⁸COR¹⁰, —SR¹⁰, —SO₂R¹⁰, —SO₂NR⁵R⁶,—NR⁸SO₂R¹⁰, C₁-C₆ alkyl or trifluoromethyl groups; R² representshydrogen or a C₃-C₇ carbocyclic group, C₁-C₈ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl group, the latter four groups may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, —OR⁴, —NR⁵R⁶ —CONR⁵R⁶, —COOR⁷, —NR⁸COR⁹, —SR¹⁰,—SO₂R¹⁰, —SO₂NR⁵R⁶ or —NR⁸SO₂R⁹; R³ represents hydrogen or C₂-C₆ alkyloptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR¹⁰ and —NR¹¹R¹²; or R² and R³represent a 3-8 membered ring optionally containing one or more atomsselected from O, S, NR⁸ and itself optionally substituted by C₁₋₃-alkyl,halogen or OR⁴; R⁴ represents hydrogen, C₁-C₆ alkyl or a phenyl groupthe latter two of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹¹ and —NR¹²R¹³; R⁵ and R⁶ independently represent a hydrogen atom ora C₁-C₆ alkyl or phenyl group the latter two of which may be optionallysubstituted by one or more substituent groups independently selectedfrom halogen atoms, phenyl, —OR¹⁴ and —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 4- to 7-membered saturated heterocyclicring system optionally comprising a further heteroatom selected fromoxygen and nitrogen atoms, which ring system may be optionallysubstituted by one or more substituent groups independently selectedfrom phenyl, —OR¹⁴, —COOR¹⁴, —NR¹⁵R¹⁶, —CONR¹⁵R¹⁶, —NR¹⁵COR¹⁶,—SO₂NR¹⁵R¹⁶, NR¹⁵SO₂R¹⁶ or C₁-C₆ alkyl, itself optionally substituted byone or more substituents independently selected from halogen atoms and—NR¹⁵R¹⁶ and —OR¹⁷ groups; R¹⁰ represents a C₁-C₆ alkyl or a phenylgroup, each of which may be optionally substituted by one or moresubstituent groups independently selected from halogen atoms, phenyl,—OR¹⁷ and —NR¹⁵R¹⁶; X is O, S or NR⁸; Y is CR¹⁸R¹⁹; Z is CR²⁰ where R²⁰represents a C₁-C₆ alkyl or a phenyl group, each of which may beoptionally substituted by one or more substituent groups independentlyselected from halogen atoms, phenyl, —OR²¹ and —NR²²R²³, or an acylgroup selected from CO₂R²¹ or CONR²²R²³; and each of R⁷, R⁸, R⁹, R¹¹,R¹², R¹³,R¹⁴ R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²² and R²³ represent ahydrogen atom, C₁-C₆, alkyl, or a phenyl group, in the manufacture of amedicament for the treatment of a chemokine mediated disease.